The key to a successful immune system is the ability of the host to maintain tolerance to many "self" antigens while still preserving the ability to react strongly to "foreign invaders". The regulation of tolerance and immunity in the periphery has been a long debated, yet remains poorly understood. One remarkable feature of peripheral tolerance is the fact that some classes of foreign antigens, when ingested or inhaled, can downregulate or prevent systemic immune reactions. Despite intense efforts, the mechanism of establishing non-responsiveness is still controversial, and the critical variables that influence tolerance induction remain poorly defined. The objective of this application is to clarify these issues by making use of the well characterized T helper cell responses to cytochrome c in mice and the recently developed peptide/MHC tetramer method of staining specific T-cells to study the regulation of systemic immune responses brought about by the oral administration of antigens and the characteristics of presentation or orally introduced antigens. The investigators goals are to understand (i) the mechanism of tolerance/immunity induction by orally introduced antigen, and (ii) the characteristics of the antigen presentation (antigen presenting cells, amount of antigen presented, the timing of antigen presentation) and their impact on the T-cell responses. To achieve these goals, the investigators will first analyze the endogenous and induced T-cell response to cytochrome c after antigen feeding, and use the information as a basis to probe the mechanism of oral tolerance/immunity induction. They will also characterize the antigen presentation in this system and determine the potential of intestinal epithelial cells (IEC) as antigen presenting cells in mucosal immunity. A better understanding of the role of immune cells in the mucosal system as well as the impact and the mechanism of orally introduced antigen on systemic immune responses is fundamental for developing therapeutic protocols for treating autoimmune diseases and allergic reactions. The information may also be important for mucosal vaccine development.